Insulin-dependent diabetes has a complex origin involving both environmental and genetic risk factors. Studies of identical twins, families with affected members, and unrelated IDDM patients indicate that susceptibility to IDDM results from environmental factors and the action of several (possibly interactive) genes. Numerous studies have documented the role of the HLA locus in IDDM susceptibility, and recent evidence strongly suggests that a second susceptibility locus exists near the insulin gene on chromosome 11. However, genetic studies in animal models which reveal as many as 5 predisposing genes, and sporadic reports of population based associations between candidate genes and IDDM suggest that additional susceptibility loci exist in humans. At this time, the number of these genes, their locations, and possible roles in IDDM are unknown. The goal of this application is to use the tools of genetic linkage analysis to identify, or exclude the existence of, such susceptibility genes. Accordingly, we propose to study 200 multiplex IDDM families with microsatellite polymorphisms spaced 10-20 cM apart throughout the genome for evidence of linkage to IDDM. In regions where linkage is detected, we will use physical mapping and cloning strategies to identify putative IDDM susceptibility genes. In regions where linkage is not detected, we will be able to assign confidence limits to our exclusion of an IDDM susceptibility gene. The work involved in mapping the entire human genome for IDDM susceptibility genes is prodigious. In order to complete this project in a timely and efficient manner, we have formed a collaboration with 3 other investigators with whom we are submitting coordinated R01 applications. This group of investigators (R. Spielman and N. Risch, co-investigators; G. Bell, and P. Concannon) will divide the task of screening the human genome, maintain a central database for the storage and analysis of all genotype information, freely share all reagents and data, and co-author all publications. While any one of these laboratories could carry out the proposed experiments independently, this collaboration should greatly speed the rate at which our goal of mapping IDDM susceptibility genes in the human can be achieved.